Thebaine is an opiate alkaloid. While thebaine is not used therapeutically itself, it can be converted industrially into a variety of therapeutically important opiate alkaloids including oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, diprenorphine, buprenorphine and etorphine. Buprenorphine, for example, is a thebaine derivative with powerful analgesia approximately twenty-five to forty times as potent as morphine, and is indicated for the treatment of moderate to severe chronic pain or for pre-operative analgesia.
Buprenorphine is made via a synthetic route that starts with the conversion of thebaine to 6,14-endo-etheno-7α-acetyltetrahydro-thebaine. In particular, thebaine has been reacted with a dienophile (e.g., methyl vinyl ketone) in the presence of an alcohol to produce the Diels Alder product 6,14-endo-etheno-7α-acetyltetrahydro-thebaine (K. W. Bentley and D. G. Hardy, J. Am. Chem. Soc., 1967, 89 (13), 3267-3273. More precisely, the Diels Alder product is a mixture of two epimers: 6,14-endo-etheno-7α-acetyltetrahydro-thebaine and 6,14-endo-etheno-7βacetyltetrahydro-thebaine. The reported ratio of the 7-α epimer to the 7-β epimer formed by the aforementioned process is 98.44:1.56, respectively. Of these two epimers, the 7-α epimer is an important early intermediate used to produce buprenophine, and the 7β epimer is an impurity that results in the formation of unwanted side compounds. For example, if the 7-β epimer isn't isolated it carries on in the buprenorphine synthesis to produce 7-β-buprenorphine, an impurity, at levels higher than currently prescribed guidelines established by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). As such, even trace amounts of the 7-β epimer are undesirable in a final product. So while the traditional Diels Alder conversion of thebaine to 6,14-endo-etheno-7α-acetyltetrahydro-thebaine results in the formation of a relatively high yield of the Diels Alder product, it also produces unacceptably high levels of the 7-β epimer in the key intermediate. A need therefore exists for a process that provides a high yield of 6,14-endo-etheno-7α-acetyltetrahydro-thebaine while minimizing the formation of 6,14-endo-etheno-7β-acetyltetrahydro-thebaine.